Methods and formulations for the efficient delivery of water-insoluble drugs by nebulizer

ABSTRACT

Formulations, methods and devices for producing formulations and methods for nebulizer delivery of formulations of water-insoluble drugs are provided. Also provided are methods for minimizing wastage of drugs administered by nebulizer, and for the achievement of quantitative dosing with diluent from a mass marketed formulations, which because of the mass market is much less costly per dose than formulations manufactured specifically for much lower volume medical use.

This patent application is the National Stage of InternationalApplication No. PCT/US00/34304, filed Dec. 15, 2000, which claims thebenefit of priority to U.S. Provisional Application No. 60/171,997,filed Dec. 23, 1999.

BACKGROUND OF THE INVENTION

Asthma is a chronic inflammatory disorder of the airways in whichinflammation contributes to hyper responsiveness to allergic andirritant stimuli, to airflow limitation, to a broad spectrum ofrespiratory symptoms, and to disease chronicity. Features of thisinflammatory process include denudation of airway epithelium, edema,recruitment and activation of various types of migratory inflammatorycells, and increased basement membrane collagen deposition which isbelieved to be the cause of the chronic changes known as asthmaticairway remodeling.

Topically acting corticosteroids are the most potent and consistentlyeffective long-term control medication for asthma. Their broad action onthe inflammatory process may account for their efficacy as preventivetherapy. Their clinical effects include reduction in severity ofsymptoms, improvement in peak expiratory flow rate and spirometry,diminished hyper responsiveness of airways, prevention of exacerbations,and possibly the prevention of airway wall remodeling. Further, thereare data suggesting that earlier treatment with inhaled topically actingsteroids, measured in years following diagnosis of asthma, results inbetter long term outcome and lower cumulative aggregate dose of steroidsneeded for optimal control.

Topically acting corticosteroids for asthma are generally administeredas aerosolized droplets released into a spacer or holding chamber from apressurized metered dose inhaler, and slowly inhaled from expiration orresting lung volume to maximum inspiratory volume by the patient, whothen holds his breath for at least 10 seconds. Alternative devices aredry powder inhalers, activated by sucking from expiration or restinglung volume to maximal inspiration, followed by similar breath-holding.

The most widely favored delivery system for inhaled asthma medicationsfor children who are too young to effectively use metered dose aerosolsor dry powders, and for patients of any age whose airways are soirritable that they will cough out medications inhaled from metered doseor dry powder inhalers, is the compressor-driven jet nebulizer. Thisdevice generates a mist of droplets of medication in aqueous solutionwhich is inhaled through either a mouthpiece or a mask. The market forthis type of drug delivery system is large enough to have supported thedevelopment of inexpensive equipment for home use that is easy to useand reasonably efficient at delivering particles in the size rangeneeded for effective topical treatment of asthma. The distributionsystem for this type of equipment makes it available at competitiveprices throughout the United States. There are also other types ofnebulizers designed for the same market, one being ultrasonic, in whichmist is generated by a small plate vibrating at ultrasonic frequencyinstead of by turbulence created by a jet of compressed air. Some maybecome more popular in the future as ways to generate aerosols withdifferent particle size distribution. It is anticipated that most willbe designed to compete with the jet nebulizer market, for nebulizationof liquids with nebulization characteristics approximating those ofphysiologic saline, and in volumes of 1 to 5 ml.

Topically acting corticosteroids are not sufficiently water-soluble todeliver effective treatment doses in practical volumes of nebulizablesolution. This makes the most potent and consistently effectivelong-term control medications for asthma unavailable to young children,for whom early treatment with these medications offers the greatestpotential for long term reduction in severity.

There have been previous attempts to overcome this problem.

Metered dose aerosol holding chambers have been designed with valves andmasks, to be placed over a child's mouth and nose, so that droplets ofmedication sprayed into the chamber from an “adult” metered dose asthmainhaler will be inhaled in the course of either the child's normalbreathing, or (as many young children resist the devices) the child'scrying. Some parents, some physicians and some investigators find thesedevices convenient and effective, many find them much less so.

Unit doses of small, readily absorbable particles of water-insoluble,topically-acting steroids have been packaged with aqueous vehicles fornebulizer administration as aqueous suspensions. Such products haveshelf life stability problems because of agglomeration of small drugparticles into larger ones over time.

The recently published international PCT application WO 99/44594discloses a drug delivery system in which water-insoluble drugs areprepared as lipid-water emulsions, freeze-dried, and dispersed in waterfor nebulization. Emulsions, like suspensions, are two-phase systemswhich, over time, undergo physical transition to lower energy states.Maintenance of a boundary between phases takes energy, so that a lowerenergy state can be achieved by reducing the surface area of thisboundary. For a solid-in-liquid suspension the physical transition thattakes place over time is particle agglomeration. For an emulsion, it isdissociation.

The present invention is an application of a model based on principlesof physical chemistry, for the design of formulations of topicallyacting corticosteroids and other water-insoluble drugs for nebulizerinhalation in aqueous vehicles, which avoid the problems of particleagglomeration and dissociation of emulsions. The present invention alsoallows the economy of multiple dose packaging of concentrated drug in astate that is both ready-to-use and physically stable.

SUMMARY OF THE INVENTION

An object of the present invention is to provide formulations andprocedures for preparing formulations using commercially marketedsterile saline, sterile buffered saline or other sterile aqueousdiluents, as vehicles for the nebulizer delivery of water-insolubledrugs. In the present invention, a water-insoluble drug is dissolved ina non-aqueous solvent at a sufficiently high concentration that thevolume of non-aqueous solvent per dose of drug is non-toxic. Suchvolumes are insufficient to operate presently available nebulizers.However, it has now been found that treatment doses in measured smallvolumes of these non-aqueous solutions can be mixed, immediately priorto nebulization, with larger volumes of aqueous vehicles. This resultsin formulations of sufficient volume to be administered effectively viacommercially available nebulizers. These formulations exhibitcharacteristics of a two-phase liquid-liquid suspension. Dispersion of asmall volume of the discontinuous, non-aqueous phase is maintained bythe mixing action of the nebulizer in a large volume of continuousaqueous phase for the 10–20 minutes needed for administration of thetreatment dose. The aqueous phase of the nebulizer formulation may alsocontain additional water-soluble drugs to be delivered to a patientconcurrently with the water-insoluble drug dissolved in the non-aqueousphase of the suspension.

Another object of the present invention is to provide a method forimproving delivery efficiency of any drug, water soluble or not,administered via non-continuous-flow jet nebulizer or ultrasonicnebulizer technology. This method involves “washing into the patient”with an extra aliquot of sterile diluent, most of the average of 40% ofeach dose left in present-day jet and ultrasonic nebulizers when thevolume remaining in the device drops below the threshold needed foreffective mist generation. This is done when the nebulizer stopsgenerating mist, by adding additional sterile aqueous diluent to thenebulizer chamber, without additional drugs, restarting the nebulizer,and having the patient inhale the resulting aerosol until mistgeneration stops, again.

Another object of the present invention is to provide a device forquantitative measurement and dosing of sterile diluents such as bufferedsterile saline from pressurized multi-dose, non-metered-dose canisters.

Yet another object of the present invention is to provide a device forclean, accurate and inexpensive measurement and dosing of small volumesof drugs in concentrated solution from multi-dose bottles.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1 a, 1 b, and 1 c show an embodiment of a measuring device forquantitative measurement and dosing of sterile diluents in preparationof formulations of the present invention. In this embodiment, thesupport of the device comprises two pieces, a trapezoidal rest, tosupport the tube at a selected angle and a triangular brace whichprovides structural support for the rest. FIG. 1 a provides a side viewdiagram of the tubular body in its resting position in the support. FIG.1 b provides an end-view diagram of the measuring device in the sameposition. FIG. 1 c provides a bottom view of this device.

FIGS. 2 a, 2 b, and 2 c show another embodiment of a measuring devicefor quantitative measurement and dosing of sterile diluents inpreparation of formulations of the present invention. In thisembodiment, the support of the device comprises two triangular wingsupon which the tubular body rests and a trapezoidal bridge locatedbetween the wings for support. FIG. 2 a provides a side view diagram ofthe tubular body in its resting position in the support. FIG. 2 bprovides an end-view diagram of the measuring device in the sameposition. FIG. 2 c provides a view from the bottom, perpendicular to thelong excess of the tubular portion of the device.

FIG. 3 provides a cross-sectional side view of a device to facilitatemeasuring and dosing small volumes, i.e. 0.05 to 0.5 ml, ofnon-water-soluble drugs from a multi-dose bottle for nebulizerformulation in a clean, inexpensive and accurate manner.

DETAILED DESCRIPTION OF THE INVENTION

Water-insoluble drugs, such as topically acting asthma corticosteroids,are often sufficiently soluble in non-aqueous solvents such as, but notlimited to, various glycols and/or alcohols alone or in combination, sothat therapeutic doses can be in non-toxic solvent volumes of 0.05 to0.5 ml. Such solutions are physically stable (i.e., they do notdissociate or agglomerate over the shelf life of the product) and theycan be packaged inexpensively in multi-dose containers. They cannot beadministered in this form with presently available nebulizers, however,because non-toxic volumes of their non-aqueous vehicles are insufficientfor the operation of currently available nebulizers.

The present invention relates to new formulations comprisingwater-insoluble drugs and methods of delivering these formulations vianebulizer. In the present invention, single doses of water-insolubledrugs dissolved in small volumes of non-aqueous solution are mixed withlarger volumes of aqueous vehicles just prior to nebulization. Theaqueous vehicle may also contain water-soluble drugs to be administeredconcurrently with the water-insoluble drug. Accordingly, multipleprescribed inhaled medications can often be administered together usingthe formulations described herein.

What results is a formulation comprising a safe, small volume ofnon-aqueous vehicle containing water-insoluble drug, suspended in asufficiently large volume of aqueous vehicle for effective delivery withproven, presently available nebulizer technology. While the exactmolecular structure of the resulting mixture has not been determined,the physical behavior and/or characteristics of the mixture are that ofa two-phase liquid-liquid suspension. By “nebulizer technology” it ismeant to include both reliable and inexpensive jet nebulizers that arewidely used at this time for delivery by inhalation of water-solubledrugs to infants and children with asthma, and improvements of the sameor functionally comparable technologies such as ultrasonic nebulizers,to increase efficiency, alter drug deposition within the respiratorytract by varying particle size, and/or reduce treatment time.

The same principles of physical chemistry govern boundary behavior ofall two-phase systems. Previously developed formulations for nebulizeradministration of water-insoluble drugs in aqueous media involve thegeneration of a suspension prior to packaging. All such formulationswill slowly dissociate and/or agglomerate during storage without theinput of additional energy to maintain dispersion. With the presentinvention, however, a different outcome is achieved because ofdifferences in both the timing of dispersion and the energy required toachieve and maintain dispersion.

In the present invention, the aqueous and non-aqueous components of theformulation are stored separately as stable one-phase solutions, andmixed immediately prior to nebulization. The energy required to achievedispersion is sufficiently low when both aqueous and non-aqueous phasesare low viscosity liquids, as in the formulations of the presentinvention, that dispersion can be created and maintained for what isusually a 10 to 20 minute duration of treatment, by the mixing action ofthe nebulizer used for administration of the drug.

It takes energy to maintain the boundary between the phases of atwo-phase suspension. In the absence of an external source of thisenergy, every random molecular movement that reduces the total surfacearea of boundary between the two phases, will slightly disaggregate it,as the energy released by the reaction is dissipated into theenvironment as heat, and unavailable to energize molecular movement inthe opposite direction. Accumulation of these spontaneous molecularmovements over time results in particle agglomeration in solid particlesuspensions, and in disaggregation of emulsions. Disaggregation does notoccur with the formulation of the present invention because the aqueousand non-aqueous components are not mixed until the time of nebulization,and the energy needed to both create and maintain dispersion is providedby the operation of the nebulizer.

Examples of topically acting steroids for which this invention now makespossible the development of stable preparations for nebulizer useinclude, but are not limited to, beclomethasone, budesonide,flunisolide, fluticasone, mometasone and triamcinolone.

For the purposes of this invention, by “safe” it is meant a volume ofnon-aqueous solvent which is sufficiently small in quantity to poseeither no significant risk of toxic effects, or a smaller risk of toxiceffects than the alternative treatments the same patients would need inthe absence of treatment using the present invention. As will be obviousto those of skill in the art upon this disclosure, the upper volumelimit of “safe” may be different for different solvents and for infantsand children of different ages. For any specific new drug application,the sponsor would have to satisfy the F.D.A. (or, for use in othercountries, the appropriate regulatory office or administration) that theproposed volumes of the individual proposed solvent are in fact safe.

By “small” volume of non-aqueous solvent, it is meant a volume smallenough not to perturb the nebulization characteristics of the mixture incomparison to the nebulization characteristics of the continuous aqueousphase if nebulized alone. “Small” is any volume that would become thediscontinuous phase of what in the formulations of the present inventionbehaves as a two-phase liquid-liquid suspension which nebulizes withapproximately the surface tension, droplet size, mist generation rateand other physical properties of the continuous, aqueous phase.

By “large” volume of aqueous phase, it is meant a volume large enough tooperate the nebulizer. The device that is provided when a physicianprescribes a compressor-driven nebulizer or a compressor-driven jetnebulizer for asthma, usually operates efficiently with a fill volume ofup to 4 ml of a liquid with nebulization characteristics of physiologicsaline. It stops generating mist, depending upon the model, when thebody remaining in the chamber drops below 0.5 to 1.0 ml. Accordingly,for most present nebulizers, by large volume it is meant from about 2.5to about 4 ml. Smaller operating volumes leave an unacceptably highpercent of content in the chamber at the end of mist generation. Volumesmuch larger than about 4 ml do not allow enough room in presentlyavailable nebulizer chambers for effective mist generation. Since thephysical properties of the aqueous phase are major determinants of thesurface tension, droplet size, mist generation rate and other physicalproperties of formulations that behave as two-phase, liquid-liquidsuspensions, the volume of this phase can be adjusted within the 2.5 to4 ml range to optimize these properties.

The economy of packaging water insoluble-drugs as concentrated solutionsin multi-dose containers is practical for the overwhelming majority ofnebulizer applications, as the delivery systems in which they are usedmust be clean but not sterile. The equipment, after post-use cleaning,may be stored dry but not sterile. Aqueous diluents or vehicles used inlarge volume must be kept sterile; once opened, concentrated additivesmay be kept clean, but not necessarily sterile, with preservatives, aslong as the quantities of preservatives needed to prevent microbialovergrowth, like the quantities of non-aqueous solvent needed todissolve therapeutic doses of non-aqueous drugs for two-phaseliquid-liquid suspension, are sufficiently small to be non-toxic andhave no other adverse effects when diluted for nebulization. “Otheradverse effects” would include impairment of nebulizer operation bysufficient concentrations of quaternary ammonium disinfectants which actas detergents to reduce surface tension, impair mist generation andthereby prolong treatment time. Most non-aqueous solvents haveantimicrobial properties of their own, reducing the quantity of otherpreservatives needed for that purpose.

The present invention also relates to a method for improving deliveryefficiency of any drug delivered via a nebulizer. Most present daynebulizers stop generating aerosol when the volume remaining in thechamber drops below approximately 1 ml. This is a significant fractionof a 2.5 ml dose of most unit dose medications marked for use with thesedevices. However, if the drug is packaged as a concentrate to be mixedwith an aqueous diluent for delivery, when the nebulizer stopsdelivering aerosol and begins to sputter, indicating that the remainingvolume has dropped below the threshold for effective operation, anotherdose of aqueous diluent can be added and nebulized into the patient, towash in the majority of the remaining medication. With presentlyavailable nebulizers, volumes of 2.5 to 3.5 ml are optimal for thisstep. As will be obvious to those of skill in the art upon reading thisdisclosure, this method of minimizing drug wastage and improving drugdelivery efficiency is also useful with nebulizable formulations otherthan those described herein.

The pharmaceutical industry is beginning to explore inhalation ofnebulized dosage forms as a route of systemic delivery of various drugsfor which there is not always effective and predictable oral absorption.Some are water-soluble, others are not. The formulations and methods ofthe present invention for drug delivery, as well as the methods forminimizing drug wastage upon delivery of a nebulized drug, are clearlyapplicable to delivery by nebulizer of such other drugs.

Dosing by mask to an infant or young child is effective but notquantitatively reproducible, because of variable loss of nebulized drugduring expiration and variable deposition of each inspired “bolus”because of variable depth of inspiration and duration of breath-holding.

However, dosing by mouthpiece to an older child or adult, with anebulizer chamber or compressor-chamber combination delivering a highand reproducible fraction of respirable particles and with a lowresidual volume at the end of aerosol generation, and a thumb valve tointerrupt mist generation and prevent drug loss during breath-holdingand expiration, is much more reproducibly quantitative. If drug is dosedinto the nebulizer chamber in a volume of 3.5 ml, and residual volume ofthe nebulizer chamber is 0.5 or 1.0 ml (the lower value achievable withcertain models of nebulizer chamber), the fraction of drug left in thenebulizer at the end of treatment will be 14.3 or 28.6%. Washing in thisleft-over drug with 3 ml of sterile or buffered sterile saline inaccordance with the method described herein will reduce drug wastage to2.4% or 9.5%. Accordingly, using the formulations and methods of thepresent invention it is now feasible for developers of both respiratoryand non-respiratory drugs to quantitatively deliver drugs by inhalationto older children and adults using economical and reliable nebulizersystems that are already available.

The developer of a specific drug application has various options inusing the formulations and methods of this invention.

For example, in one embodiment, a water-insoluble drug can be mixed witheither a unit dose formulation of a water-soluble drug in aqueousdiluent prescribed for concurrent administration, or with a commerciallyavailable sterile saline or buffered sterile saline diluent, with orwithout addition of a concentrated, small volume of any otherwater-soluble drug also prescribed for concurrent administration. Inthis embodiment, it is preferred that any remaining drug or drugs in thenebulizer chamber be washed in via an additional aliquot of commerciallyavailable sterile saline or buffered sterile saline diluent.

In another embodiment, for a water-soluble drug, the drug can besupplied as a concentrate for dilution with a commercially availablesterile saline or buffered sterile saline diluent, or as a pre-packagedunit dose. In this embodiment, it is also preferred that any remainingdrug in the nebulizer chamber be washed in via an additional aliquot ofcommercially available sterile saline or buffered sterile salinediluent.

Commercially available formulations of sterile saline or bufferedsterile saline include: individually sealed 3 ml unit dose ampules witha present cost to the user of approximately $0.30/ampule ($0.10 per ml);8 ounce pressurized metered dose, multi-dose canisters of sterile salinemanufactured as a nebulizer diluting solution, dispensing 1 ml each timeit is pressed, at a cost of approximately $0.042 per ml; and 12 ouncepressurized non-metered dose, multi-dose canisters of borate-bufferedsterile saline sold as a cleaning solution for contact lenses, whichranges in cost from approximately $0.009 to $0.015 per ml.

A manufacture of formulations of the present invention can achieve thegreatest reduction in combined insurer plus user cost, without reducingits own revenues per dose sold, by obtaining FDA certification of itsdrug for use with the least expensive formulation of sterile saline orbuffered sterile saline diluent. Currently, 12 ounce pressurizednon-metered dose, multi-dose canisters of buffered sterile salinemarketed as a cleaning solution for contact lenses are the leastexpensive formulations. The manufacturer of a drug using this product asa diluent can package each multi-dose bottle of concentrated solution ofdrug with a quantitative measuring device and instructions for its usewith pressurized, non-metered-dose, multi-dose canisters of sterilesaline.

The design features of a quantitative measuring device useful in thepresent invention can be best understood as features to implement thefollowing performance specification. The device shall quickly,accurately and reproducibly measure and dispense into a nebulizerchamber a pre-determined (i.e. not user adjustable) volume in theseveral milliliter range of a physiologic saline or buffered salinesolution that has just been released from a pressurized canister. Sincethe saline will contain effervescing bubbles of trapped propellant as itis dispensed into the device, the device must accommodate the volume ofbubbles and allow them to dissipate without affecting the accuracy ofthe volume it then dispenses.

Representative embodiments of a quantitative measuring device for use inpreparing formulations of the present invention are depicted in FIGS. 1a, 1 b and 1 c and in FIGS. 2 a, 2 b and 2 c. In simplest form, themeasuring device comprises a tubular body 1, preferably cylindrical inshape as this geometry is easy to keep clean and is less favorable fortrapping of bubbles as compared to polygonal shapes. The bottom of thetube 2 is closed and is preferably hemispherical in shape, again forease in cleaning and to prevent trapping of bubble in corners. The topof the tube 5 is open. In one embodiment of the invention, the top ofthe tube 5 is tapered inward, in similar fashion to the top of a jar, tominimize spills when the device is tapped to dislodge bubbles. Inanother embodiment, the tubular body of the device 1 is minimallyconical, increasing in diameter from bottom to top by up to 1 to 2% perunit length. This design should allow a less expensive fabricationprocess. The reduced spill tendency achieved by a narrowed neck in thefirst embodiment is achieved in this embodiment by increasing itslength. The following support designs or any other support shape thatmeets the performance specifications described herein can be used inboth of these embodiments.

A support 4 is molded into the tubular body 1 to hold the tube at aconvenient angle to allow bubbles of propellant in the diluent toeffervesce without displacing volume to be measured from the tube. Inone embodiment, as depicted in FIGS. 1 a, 1 b, and 1 c, the support 4comprises two pieces, 4 a and 4 b which form a trapezoidal rest 4 awhich supports the tube at a selected angle, and a triangular brace 4 bwhich provides structural support for the rest. In another embodiment,as depicted in FIGS. 2 a, 2 b and 2 c, the support 4 comprises twotriangular wings 4 c and a trapezoidal bridge 4 d located between thewings for support. In both embodiments, a proturbance 6 is placed on theouter surface of the hemispherical bottom 2 of the tubular body 1. Thisproturbance 6 provides a resting point for the device when placed on aflat surface at an angle against the support. The tubular body 1 alsocomprises a square hole 3 with sides parallel and perpendicular to thelong axis of the tubular body 1 and centered on the side of the tubewhich is pointed up when the device is rested on its support 4. The hole3 is sized and positioned so that when the device is filled withslightly more diluent than a desired dose and positioned vertically, thelevel of diluent will be above the bottom of the hole 3. In a preferredembodiment, the device further comprises proturbances, 7 a and 7 b, onthe outer surface at the top of the tubular body, and proturbance 10 onthe outer surface at the bottom of the tubular body to facilitategripping the device with the thumb below proturbance 7 a and the middlefinger below proturbance 7 b, to expel extra diluent through the hole 3by gentle tapping. The distance 8 from the bottom 2 of the tubular body1 to the bottom of the hole 3 is fixed so that the device will deliverthe desired volume of diluent when used as described herein. The devicemay further comprise an optional fill line 9 on the outer surface of thetubular body 1 which provides a guide to slightly overfill the tubularbody 1 from a non-metered, dose-pressurized canister, to allow foreffervescence and subsequent delivery of an accurate dose, with minimalwastage. The device may optionally further comprise additionalproturbances 11, located on the outer surface of the tubular body 1 atthe top 5 and bottom 2 which serve as finger grips to grasp the devicewhen rocking it on its support 4, to let it gently bounce on proturbance6 to dislodge any bubbles that may adhere to the inner surface aftercompletion of effervescence. Users may alternatively press down onproturbance 7 a to rock the device on its support and let it fall back,to dislodge any bubbles.

To use this device, sterile saline or sterile buffered saline diluent isdispensed into the device from the non-metered, dose-pressurizedcanister in which it is supplied. The device is tipped to its desiredfill angle as it is filled, to keep its contents from spilling outthrough hole 3. The device is filled to the fill line 9, and placed on aflat surface to allow effervescing bubbles to rise to the surface of theliquid in the device. Any bubbles that may have adhered to the innersurface of the device can be dislodged by tilting the device onto itssupport and letting it fall back, so that the proturbance 6 fallsagainst the surface on which the device rests thereby jarring thebubbles loose. The device is then picked up, held over the sink, rotatedto a vertical position, and proturbance 10 is gently tapped against theinside wall of the sink to jostle diluent in excess of the desired filllevel out of hole 3. Proturbances 7 a and 7 b are incorporated into thisinvention to reduce the risk of the device slipping out of the user'shand, when it is tapped against the inner side wall of a sink to expelexcess liquid. The remaining content of the device is then poured intothe nebulizer chamber, either before or after other medications areadded or as a chaser after the nebulizer has stopped generating mist.

If the geometry of a nebulizer is such that the support of the measuringdevice gets in the way of pouring from the measuring device into thechamber, the diluent may first be poured into a medicine cup and theninto the nebulizer chamber. Accordingly, a manufacturer wishing tominimize the possibility of having the protruding support of the diluentdose-measuring device interfere with pouring into certain models ofnebulizer chambers may also supply a small plastic medicine cup togetherwith the device, with a multi-dose bottle of the drug.

The measuring device of the present invention is designed so that thevolume of diluent or chaser in the measuring device, which is thenpoured into the receptacle, is accurate and reproducible, independent ofthe initial volume of overfill and independent of tapping pressure andtechnique.

The manufacturer of drugs for nebulizer formulation which are providedin multi-dose bottles containing a concentrated solution of drug canalso include a dosing device to facilitate the clean, inexpensive andaccurate measurement and dosing of small volumes of concentrated drugsolution from the multi-dose bottle, into the nebulizer chamber formixing with large volumes of aqueous media to form the two-phaseliquid-liquid suspension. The performance specification for this deviceis that it be able to accurately measure and dispense volumes from 0.05to 0.5 ml, drawn from a multi-dose bottle, that is be as easy to keepclean as the graduated plastic dropper tips presently supplied withconcentrated aqueous multi-dose nebulizer formulations for which dosevolumes range from 0.25 to 0.5 ml, and that it be inexpensive tomanufacture and distribute. The same device may be used for accuratedosing of similarly small volumes of water soluble drugs in aqueousmedia, extending downward from about 0.25 ml to 0.05 ml the range ofclean, inexpensive and accurate measurement of small volumes of alldrugs for nebulizer administration.

This device of the present invention comprises a screw-on cap for amulti-dose medicine bottle, either incorporating a gasket or with anopen top and holding in place a gasket with a flexible seal, impermeableto its liquid contents and preferably transparent, to fit around theshaft of a mass-produced, plastic 0.5 ml medicine syringe so that thesyringe can slide in and out of the bottle. The syringe is similar tothose manufactured for individuals with diabetes to self-inject insulin,except that for this use it will be provided either with no needle orwith a relatively large bore, blunt tip needle.

The device, as depicted in FIG. 3, comprises the components and elementsdescribed above. Namely, this device comprises a screw-on cap 11, agasket 12 fitted into the top of the screw-on cap; and a liquid tightseal 13 which fits around the shaft of a plastic syringe, allowing thesyringe to slide in and out of the bottle. It combines the cleanlinessin repeated use of an ordinary medicine dropper top, which need never beput down anywhere but inside its clean bottle, the accuracy of asyringe, and the economy of using a product that is already massproduced for a very large market.

Different plastic syringes may be made with silicone lubricants ofdifferent composition, or with no lubricant at all. In selecting asyringe for this use with non-aqueous media, a drug manufacturer willhave to ensure that syringe lubricant is not dissolved by thenon-aqueous medium employed, making the syringe stick and exposing thepatient to inhalation of lubricant.

EXAMPLE

A solution of flunisolide dissolved in a mixture of propylene andpolyethylene glycol is marketed for topical use as a nose spray inallergic rhinitis. This solution may be administered by nebulizer as thesmall volume, non-aqueous phase of what behaves as a two-phaseliquid-liquid suspension in aqueous media, as described herein.

This formulation of flunisolide has been demonstrated to offer youngchildren the benefit of effective nebulized topical steroid therapy forasthma for the first time. In doses of 50 to 100 μg given up to 4 timesper day, this formulation has proven convenient, effective and free ofapparent adverse effects in the treatment of multiple patients, manyover relatively long term treatment intervals. Both physician andparents have observed improved control of asthma, reduced need for acutecare, reduced need for oral steroids, and reduced need for hospital andemergency department care in more than one hundred patients treated withthis formulation of the present invention.

For these patients, a measured volume, typically 0.25 to 0.5 ml, offlunisolide dissolved in a mixed glycol non-aqueous phase was mixed with2.5 to 3.5 ml of aqueous phase consisting of a physiologic or bufferedphysiologic saline solution or a unit dose formulation of aco-administered water-soluble drug in aqueous solution, with or withoutother water-soluble drugs added as measured volumes of multi-doseaqueous formulations.

When the nebulizer began to sputter, indicating insufficient remainingvolume for effective aerosol generation, the parent or patient wasinstructed to add an additional 2.5 to 3.5 ml of sterile saline orsterile buffered saline, from a pressurized, multi-dose container.

Patients in the treatment group reported in this example generally hadinsurance coverage for medications, but had to purchase diluentout-of-pocket. With an average treatment frequency for the more than 100patients of two treatments per day for an average treatment intervalgreater than one year, the availability of sterile buffered salinediluent at a cost of approximately $0.01 per ml, dosed with a slightlyless precise measuring device than that described herein, was a majorenhancer of compliance with prescribed treatment.

1. A nebulizer device, wherein said device contains a formulation foradministration of a water-insoluble drug via the nebulizer consistingessentially of: (a) a entail volume of a solution of water-insolubledrug dissolved in a nonaqneous solvent, said small volume of solutionnot perturbing nebulization characteristics of a mixture of aqueousmedia and the small volume of solution in comparison to nebulizationcharacteristics of the aqueous media if nebulized alone; and (b) a largevolume of aqueous media, said large volume of aqueous media being largeenough to operate the nebulizer; wherein, prior to administration, saidsmall volume of solution has been mixed with said large volume ofaqueous media to form a mixture that behaves as a two-phaseliquid-liquid suspension in which dispersion of the solution in theaqueous media is maintained by mixing action of the nebulizer.
 2. Thenebulizer device of claim 1 wherein the aqueous media of the formulationcomprises a water-soluble drug to be administered concurrently with thewater-insoluble drug.
 3. A method for delivery of a water-insoluble drugvia a nebulizer to a patient consisting essentially of: (a) dissolving awater-insoluble drug in a small volume of nonaqutous solvent to form adrug solution, said small volume of nonaqueous solvent not perturbingnebulization characteristics of a mixture of aqueous media and the smallvolume of nonagusous solvent in comparison to nebulizationcharacteristics of the aqueous media if nebulized alone; (b) mixing thedrug solution with a large volume of aqueous media to form a mixturethat behaves as a two-phase liquid-liquid suspension, said large volumeof aqueous media being large enough to operate the nebulizer; and (c)delivering this mixture to the patient via the nebulizer with mixingaction, the driving energy of which both creates and maintainsdispersion of the drug solution in the aqueous media during the periodof drug delivery by inhalation.
 4. The method of claim 3 wherein theaqueous media comprises a solution of one or more water-soluble drugs tobe administered concurrently with the water-insoluble drug.
 5. A methodfor delivery of a water-insoluble drug via a nebulizer to a patientconsisting essentially of: (a) dissolving a water-insoluble drug in asmall volume of nonaqueous solvent to form a drug solution, said smallvolume of nonaqusous solvent not perturbing nebulization characteristicsof a mixture of aqueous media and the small volume of nonaqueous solventin comparison to nebulization characteristics of the aqueous media ifnebulized alone; (b) mixing the drug solution with a large volume ofaqueous media to form a mixture that behaves as a two-phaseliquid-liquid suspension, said large volume of aqueous media being largeenough to operate the nebulizer; (c) delivering this mixture to thepatient via the nebulizer with mixing action, the driving energy ofwhich both creates and maintains dispersion: of the drug solution in theaqueous media during the period of drug delivery by inhalation; and (d)adding an aliquot of sterile saline or sterile buffered saline to anebulizer chamber after delivering the drug mixture to the patient tofurther mix with any remaining drug in the nebulizer chamber andnebulizing the remaining drug mixture into the patient.
 6. A nebulizerdevice, wherein said device contains a formulation for administration ofa drug via the nebulizer, the formulation consisting essentially of asmall volume of a solution of a drug requiring dilution prior toadministration, said small volume of solution of drug not perturbingnebulization characteristics of a mixture of aqueous vehicle and thesmall volume of solution of drug in comparison to nebulizationcharacteristics of the aqueous vehicle if nebulized alone, and a largevolume of aqueous vehicle, said large volume of aqueous vehicle beinglarge enough to operate the nebulizer; wherein, prior to administration,said small volume of solution of drug requiring dilution prior toadministration has been mixed with said large volume of aqueous vehicleto form a that behaves as a two-phase liquid-liquid suspenion suitablefor administration via the nebulizer.